Piezo1 contributes to ulcerative colitis via macrophage pyroptosis through TXNIP/NF-kB/NLRP3 axis

The mechanosensor Piezo1 modulates the response of macrophages to lipopolysaccharide (LPS) stimulation. This study investigated the role of Piezo1 in the context of ulcerative colitis (UC). RNA-sequencing of a murine colitis model revealed an enrichment of genes associated with mucosal inflammation and macrophage pyroptosis. The expression of TLR4 and Piezo1 was elevated in colonic macrophages of colitis mice. Conversely, colonic expression of thioredoxin-interacting protein (TXNIP), a known repressor of NF-kB activity, was reduced. Furthermore, the NF-kB/NLRP3 pathway was activated, and levels of the pyroptosis executioner Gasdermin D N-terminal (GSDMD-NT) were increased. Consistent with the murine data, elevated Piezo1 expression and decreased TXNIP expression were also observed in colonic macrophages from UC patients. These findings were recapitulated in an in vitro model of LPS-stimulated macrophages. In vitro experiments demonstrated that Piezo1 suppression upregulated TXNIP, which inhibited NF-kB activity and subsequently reduced NLRP3-mediated pyroptosis. Importantly, pharmacological blockade of Piezo1 attenuated both pyroptosis and mucosal inflammation in the murine colitis model. In conclusion, Piezo1 is a critical driver of mucosal inflammation in UC, promoting pyroptosis via the TXNIP/NF-kB/NLRP3/GSDMD pathway. Therefore, targeting Piezo1 represents a viable therapeutic strategy to alleviate inflammation in ulcerative colitis.